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The Journal of Neuroscience, April 29, 2009, 29(17):5508-5515; doi:10.1523/JNEUROSCI.4288-08.2009

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Behavioral/Systems/Cognitive
TrkB Signaling Is Required for Both the Induction and Maintenance of Tissue and Nerve Injury-Induced Persistent Pain

Xidao Wang,¹ Joseline Ratnam,² Bende Zou,² Pamela M. England,² and Allan I. Basbaum¹

¹Departments of Anatomy and Physiology and W. M. Keck Foundation Center for Integrative Neuroscience, and ²Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158

Correspondence should be addressed to Allan I. Basbaum, Department of Anatomy, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158. Email: allan.basbaum{at}ucsf.edu

Activation of primary afferent nociceptors produces acute, short-lived pain, and tissue or nerve injury induces long-term enhancement of nociceptive processing, manifested as hypersensitivity to thermal and mechanical stimulation. Here we used a chemical–genetic and pharmacological approach to study the contribution of the receptor tyrosine kinase, type 2 (TrkB) to the generation and maintenance of injury-induced persistent pain. We performed the studies in wild-type mice and transgenic (TrkB^F616A) mice that express mutant but fully functional TrkB receptors. By injecting a small molecule derivative of the protein kinase inhibitor protein phosphatase 1 (1NM-PP1), it is possible to produce highly selective inhibition of TrkB autophosphorylation in adult mice, without interfering with the activity of other protein kinases. We report that oral administration of 1NM-PP1, at doses that blocked phosphorylation of TrkB in the spinal cord, had no effect in behavioral tests of acute heat, mechanical, or chemical pain sensitivity. However, the same pretreatment with 1NM-PP1 prevented the development of tissue- or nerve injury-induced heat and mechanical hypersensitivity. Established hypersensitivity was transiently reversed by intraperitoneal injection of 1NM-PP1. Although interfering with TrkB signaling altered neither acute capsaicin nor formalin-induced pain behavior, the prolonged mechanical hypersensitivity produced by these chemical injuries was prevented by 1NM-PP1 inhibition of TrkB signaling. We conclude that TrkB signaling is not only an important contributor to the induction of heat and mechanical hypersensitivity produced by tissue or nerve injury but also to the persistence of the pain.

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Received Sept. 8, 2008; revised Feb. 3, 2009; accepted March 20, 2009.

Correspondence should be addressed to Allan I. Basbaum, Department of Anatomy, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158. Email: allan.basbaum{at}ucsf.edu

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